Impact of Aging on CD4 Immunity to Flu. We have defined extensive age-associated defects in immune system response particulariy in naive CD4 T cells that give poor effector responses and the generation of impaired memory cells. In the first funding cycle we found that pro-inflammatory cytokines (IL-1, IL-6 and TNFa) could reverse many of the defects in effector generation, and that surrogates of viral products that stimulate immune cells, called TLR agonists, induce production of these by DC presenting antigen to the T cells. We identified IL-6 production by DC during the cognate interaction as key for increasing expansion and blocking death of responding aged naive CD4 T cells. The activation also restores memory responses to some extent. Now we will define the molecular pathways leading to the rescue of the naTve CD4 T responses using a combination of reductionist in vitro approaches and carefully designed adoptive transfer models, that will allow us to determine the cellular and molecular mechanisms involved. We will use highly tractable TcR Tg models as well as polyclonal studies to dissect mechanisms. We will analyze rescue pathways in vivo as well as extend the studies to CDS T cells in mouse and to human CD4 and CDS T cells (part of Project 5). These studies will generate important information that could contribute to the development in future of better strategies, using TLR agonists, to more effectively vaccinate the elderiy and we expect to be able to develop a unified theory of how aging develops in T cells, what defects exist and which can be overcome and how in mice and man.